Galactosylceramide
(GalCer, cerebroside) has been discovered at the end of the nineteen’s century
by J.L.W. Thudichum,
the pioneer in the chemistry of the brain (1). He
coined the term cerebrosides for a group of glycosidic substances found in
brain and composed of three building blocks :a fatty acid, a long chain base, and a
hexose. The sugar obtained by hydrolysis of the crude product was called cerebrose,
so that the name cerebroside was chosen in analogy of the plant glycosides. In
1874, Thudichum isolated cerebrosides as an impure fraction consisting of two
principal species, i.e. phrenosin and kerasin, that differed structurally by
their fatty acid component only (2) and
physically by their optical activity (phrenosin is dextrorotatory, kerasin
levorotatory). Forty years later, Thierfelder showed that phrenosin contains a
long chain α-hydroxy fatty acid, and that the acid of kerasin is lignoceric
acid, i.e. CH3-(CH2)22-COOH (3). He also identified the sugar component as
galactose. Yet the structure of the third building block, i.e. the long chain
base, remained elusive for almost fifty more years.

‘In commemoration of the many enigmas
which it presents to the inquirer’, Thudichum called it ‘sphingosine’ (in
reference to the Sphinx enigmas). Sphingosine can be easily obtained from an
alkaline hydrolysate of phrenosin. Its correct structure was established by
Carter et al. (4) in 1947.In 1958, D. Shapiro et al. published the
total synthesis of sphingosine, confirming its chemical structure as trans-D-erythro-1,3-dihydroxy-2-amino-4-octadecene
(or, according to the R/S system, trans-(2S,3R)-1,3-dihydroxy-2-amino-4-octadecene
(5). In practical, it is a C18 carbon chain (CH3-(CH2)16-CH3),
with two OH groups (at positions 1 and 3 from a terminal CH3 - don’t worry
which one, you select one when you write the structure
-), one amino group (at position 2), and a C4-C5 trans double bond. It is amazing that such a simple molecule has
resisted for decades to several generations of talented biochemists !

Carter
et al. have also introduced the term sphingolipids to designate lipids derived
from the parent base sphingosine.

Now
why is cerebroside also called galactosylceramide ? For several
reasons :

In
the central nervous system, the sugar component of cerebroside is always
galactose. In organs outside the nervous system, such as liver, spleen, or
in erythrocytes, the sugar is not galactose but glucose. Thus two classes
of cerebrosides, differing by their hexose, do exist in the body :
galactocerebroside and glucocerebroside. In some tissues (e.g. kidney),
both galacto- and glucocerebrosides are found.

So,
why galactosylceramide instead of galactocerebroside ?This is the official nomenclature
recommended by the IUPAC-IUBMB (6).
Officials do not like history (too complex, lack of logic) and consider
‘cerebroside’ as a trivial name, historically used for
monoglycosylceramides. A ceramide is formed when sphingosine is linked to
a fatty acid via an amide bond. Add a sugar (on the C1 of sphingosine),
you obtain a ceramide monohexoside = monoglycosylceramide. If the sugar is
galactose, it is called galactosylceramide and abbreviated GalCer. If the
sugar is glucose, glucosylceramide (GlcCer).

Do
not mix history and official nomenclature ! Galactosylcerebroside and
glucosylcerebroside are totally heretic and thus definitely forbidden.

GalCer and GlcCer belong to the
category of biomolecules called glycolipids, or, more acutely,
glycosphingolipids.

Phrenosin
is now called α-hydroxy-GalCer (or GalCer-HFA, i.e. GalCer with a α-hydroxy
fatty acid), and kerasin GalCer-NFA (for non-hydroxy fatty acid). Yet the
terms phrenosin and kerasin are still used by chemical suppliers. This is
an elegant hommage to the outstanding work of J.L.W. Thudichum, the
founder of brain lipid chemistry.

In
some instances, the biochemical nomenclature may be more tolerant : a
phosphoaminolipid discovered in human brain by Thudichum is a ceramide
linked to phosporylcholine. It is still called sphingomyelin, and not
phosphorylcholineceramide !

In
the central nervous system, GalCer is a major lipid constituent of myelinating
oligendrocytes, consistent with its high content in myelin (7). It is also present in neurons, particularly in
axons. Not surprisingly, chronic impairments of GalCer biosynthesis and/or
degradation can cause severe illness. GalCer is also highly expressed in
several epithelial tissues such as the mucosal intestinal epithelium, where it
may promote the adhesion of various pathogens, including HIV and prions. To
understand the biological function(s) of GalCer, you should first be more
familiar with its chemical structure, which determines its unique
physicochemical properties. In the following section, you will learn how to
draw correctly a GalCer molecule.